US6492391B1 - Crystal modification d of 8-cyano-1-cyclopropyl-7-(1s, 6s- 2,8-diazabicyclo-[4.3.0]nonan-8-yl)-6-fluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid - Google Patents

Crystal modification d of 8-cyano-1-cyclopropyl-7-(1s, 6s- 2,8-diazabicyclo-[4.3.0]nonan-8-yl)-6-fluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid Download PDF

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US6492391B1
US6492391B1 US09/914,031 US91403101A US6492391B1 US 6492391 B1 US6492391 B1 US 6492391B1 US 91403101 A US91403101 A US 91403101A US 6492391 B1 US6492391 B1 US 6492391B1
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ccdc
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diazabicyclo
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Thomas Himmler
Hubert Rast
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Bayer Animal Health GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

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  • the present invention relates to a defined crystal modification of 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, to processes for its preparation and to its use in pharmaceutical preparations.
  • CCDC 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of the formula (I) is referred to as CCDC.
  • CCDC is known from DE-A 19 633 805 or PCT Appl. No. 97 903 260.4. According to these publications, it is prepared by reacting 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid with (1S,6S)-2,8-diazabicyclo[4.3.0]nonane in a mixture of dimethylformamide and acetonitrile in the presence of an auxiliary base. Water is added to the mixture and CCDC is then extracted from water using dichloromethane and is isolated by removing the extractant. This gives a powder whose crystal modification is not unambiguous.
  • the powder is largely amorphous and can contain mixtures of different crystal modifications. If, by chance, a uniform crystal modification is formed, it is not clear how it can be extracted and obtained in a defined form. However, it is the precondition for preparing medicaments that, for an active compound which can be present in different crystal modifications, it can be stated unamibiguously which of its crystal modifications is used for preparing the medicament.
  • the partially amorphous powder which is obtained by the preparation process outlined above is furthermore hygroscopic.
  • amorphous solids, and in particular hygroscopic solids are difficult to handle when being processed pharmaceutically since, for example, they have low bulk densities and unsatisfactory flow properties.
  • the handling of hygroscopic solids requires special work techniques and apparatuses to obtain reproducible results, for example with respect to the active compound content or the stability of the solid formulations produced.
  • the invention accordingly provides the crystalline modification D of CCDC which is characterized in that it has an X-ray powder diffractogram with the reflection signals (2 theta) of high and medium intensity (>30% relative intensity) listed in Table 1 below.
  • FIG. 1 A characteristic X-ray powder diffractogram of the modification D of CCDC is shown in FIG. 1 .
  • a characteristic differential thermodiagram CCDC of the modification D is shown in FIG. 2 .
  • a characteristic differential thermodiagram of a predominantly amorphous CCDC as reported at page 5, line 25-26 is shown in FIG. 7 .
  • the CCDC modification D according to the invention differs from other forms of CCDC in a number of further properties. These properties, on their own or together with the other parameters, may also serve for characterizing the CCDC modification D according to the invention.
  • CCDC of the modification D is characterized by a melting point, determined with the aid of differential thermoanalysis (DTA), of from 261° C. to 265° C.
  • DTA differential thermoanalysis
  • CCDC of the modification D is characterized in that it has an infrared spectrum, measured in KBr, as shown in FIG. 3 .
  • Crystal modification D of CCDC is obtained by dissolving CCDC of an unknown modification or amorphous CCDC at a concentration between 1 and 3 per cent by weight in water, allowing the solution to stand until a solid precipitates out, filtering off this solid, drying the resulting water-containing product, followed by heating to a temperature above the rearrangement temperature.
  • the water-containing product can be dried by customary methods.
  • the water-containing product can be dried, for example, at elevated temperature under reduced pressure. It is also possible to carry out the drying in the presence of a customary drying agent, such as, for example, phosphorus pentoxide.
  • the temperature required for rearranging the dried sample into modification D can be determined by DTA of the dried substance. It is generally between 130° C. and 160° C.
  • CCDC of the crystal modification D is surprisingly stable and does not change into another crystal modification or the amorphous form, even on prolonged storage. For these reasons, it is highly suitable for preparing tablets or other solid formulations. Owing to its stability, it gives these formulations the desired long-lasting storage stability. Using the crystal modification D, it is therefore possible to prepare, in a defined and targeted manner, stable solid preparations of CCDC.
  • CCDC of the crystal modification D is highly active against pathogenic bacteria in the area of human or veterinary medicine. Its broad area of use corresponds to that of CCDC.
  • the X-ray powder diffractogram for characterizing the crystal modification D of CCDC was obtained using a transmission diffractometer STADI-P with a location-sensitive detector (PSD2) from Stoe.
  • the melting point of the differential thermoanalysis was obtained using the DSC 820 unit from Mettler-Toledo.
  • the sample of CCDC of the crystal modification D was heated exposed to the atmosphere in an aluminium crucible at 5 K/min.
  • the KBr IR spectrum was obtained using the 881 unit from Perkin-Elmer.
  • the examples below illustrate the invention without limiting it.
  • the solvent/base systems used in the examples below are particularly preferred.
  • the resulting solution is adjusted to pH 7 using dilute hydrochloric acid, and the solid is filtered off.
  • the filtrate is extracted three times using 20 ml of dichloromethane each time.
  • the organic phase is dried over sodium sulphate and filtered and the filtrate is concentrated at a bath temperature of 60° C. using a rotary evaporator. This gives 2.4 g of a light-brown solid which has the X-ray powder diffractogram shown in FIG. 4 and is therefore predominantly amorphous.
  • the resulting solid is suspended in a mixture of 4650 ml of ethanol and 41 g of Hünig base, and the reaction mixture is heated under reflux for 3 hours.
  • the reaction mixture is allowed to cool again to room temperature, and the solid is filtered off with suction, washed with a total of 1000 ml of EtOH and dried at from 60 to 70° C. in a vacuum drying cabinet until the weight remains constant. This gives 1130 g of a beige solid which has the X-ray powder diffractogram shown in FIG. 5 .

Abstract

The present invention relates to a defined crystal modification of 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, to processes for its preparation and to its use in pharmaceutical preparations.
Figure US06492391-20021210-C00001
The crystal modification can be distinguished from other crystal modifications of 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of the formula (I) by its characteristic X-ray powder diffractogram and its differential thermodiagram (see description).

Description

The present invention relates to a defined crystal modification of 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, to processes for its preparation and to its use in pharmaceutical preparations.
Hereinbelow, 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of the formula (I) is referred to as CCDC.
Figure US06492391-20021210-C00002
CCDC is known from DE-A 19 633 805 or PCT Appl. No. 97 903 260.4. According to these publications, it is prepared by reacting 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid with (1S,6S)-2,8-diazabicyclo[4.3.0]nonane in a mixture of dimethylformamide and acetonitrile in the presence of an auxiliary base. Water is added to the mixture and CCDC is then extracted from water using dichloromethane and is isolated by removing the extractant. This gives a powder whose crystal modification is not unambiguous. On the contrary, the powder is largely amorphous and can contain mixtures of different crystal modifications. If, by chance, a uniform crystal modification is formed, it is not clear how it can be extracted and obtained in a defined form. However, it is the precondition for preparing medicaments that, for an active compound which can be present in different crystal modifications, it can be stated unamibiguously which of its crystal modifications is used for preparing the medicament.
The partially amorphous powder which is obtained by the preparation process outlined above is furthermore hygroscopic. However, amorphous solids, and in particular hygroscopic solids, are difficult to handle when being processed pharmaceutically since, for example, they have low bulk densities and unsatisfactory flow properties. Moreover, the handling of hygroscopic solids requires special work techniques and apparatuses to obtain reproducible results, for example with respect to the active compound content or the stability of the solid formulations produced.
It is therefore an object of the invention to prepare a crystaine form of a defined modification of CCDC which, owing to its physical properties, in particular its crystal properties, is easy to handle in pharmaceutical formulations.
This object is achieved according to the invention by a novel crystalline form of CCDC which is referred to as modification D hereinbelow.
The invention accordingly provides the crystalline modification D of CCDC which is characterized in that it has an X-ray powder diffractogram with the reflection signals (2 theta) of high and medium intensity (>30% relative intensity) listed in Table 1 below.
TABLE 1
X-ray powder diffractogram of CCDC of the modification D
2 θ (2 theta)
7.6
9.5
12.8
14.2
17.5
19
19.3
19.5
20.4
21
21.8
22.6
25.2
27.5
BRIEF DESCRIPTION OF DRAWINGS
A characteristic X-ray powder diffractogram of the modification D of CCDC is shown in FIG. 1.
A characteristic differential thermodiagram CCDC of the modification D is shown in FIG. 2.
An infrared spectrum of CCDC of the modification D, measured in KBr, is shown in FIG. 3.
An X-ray powder diffractogram of the CCDC obtained by the Comparative Example at page 5 is shown in FIG. 4.
An X-ray powder diffractogram of the CCDC obtained by Example 1 at page 5, line 15-15 is shown in FIG. 5.
An X-ray powder diffractogram of a predominantly amorphous CCDC as reported at page 5, line 25-26 is shown in FIG. 6.
A characteristic differential thermodiagram of a predominantly amorphous CCDC as reported at page 5, line 25-26 is shown in FIG. 7.
Moreover, the CCDC modification D according to the invention differs from other forms of CCDC in a number of further properties. These properties, on their own or together with the other parameters, may also serve for characterizing the CCDC modification D according to the invention.
CCDC of the modification D is characterized by a melting point, determined with the aid of differential thermoanalysis (DTA), of from 261° C. to 265° C. A characteristic differential thermodiagram is shown in FIG. 2.
CCDC of the modification D is characterized in that it has an infrared spectrum, measured in KBr, as shown in FIG. 3.
Crystal modification D of CCDC is obtained by dissolving CCDC of an unknown modification or amorphous CCDC at a concentration between 1 and 3 per cent by weight in water, allowing the solution to stand until a solid precipitates out, filtering off this solid, drying the resulting water-containing product, followed by heating to a temperature above the rearrangement temperature.
The water-containing product can be dried by customary methods. Thus, the water-containing product can be dried, for example, at elevated temperature under reduced pressure. It is also possible to carry out the drying in the presence of a customary drying agent, such as, for example, phosphorus pentoxide.
The temperature required for rearranging the dried sample into modification D can be determined by DTA of the dried substance. It is generally between 130° C. and 160° C.
CCDC of the crystal modification D is surprisingly stable and does not change into another crystal modification or the amorphous form, even on prolonged storage. For these reasons, it is highly suitable for preparing tablets or other solid formulations. Owing to its stability, it gives these formulations the desired long-lasting storage stability. Using the crystal modification D, it is therefore possible to prepare, in a defined and targeted manner, stable solid preparations of CCDC.
CCDC of the crystal modification D is highly active against pathogenic bacteria in the area of human or veterinary medicine. Its broad area of use corresponds to that of CCDC.
The X-ray powder diffractogram for characterizing the crystal modification D of CCDC was obtained using a transmission diffractometer STADI-P with a location-sensitive detector (PSD2) from Stoe.
The melting point of the differential thermoanalysis was obtained using the DSC 820 unit from Mettler-Toledo. Here, the sample of CCDC of the crystal modification D was heated exposed to the atmosphere in an aluminium crucible at 5 K/min.
The KBr IR spectrum was obtained using the 881 unit from Perkin-Elmer. The examples below illustrate the invention without limiting it. The solvent/base systems used in the examples below are particularly preferred.
COMPARATIVE EXAMPLE
A mixture of 3.07 g of 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.39 g of (1S,6S)-2,8-diazabicyclo[4.3.0]nonane, 2.24 g of 1,4-diazabicyclo[2.2.2]octane (DABCO), 29.5 ml dimethylformamide and 29.5 ml of acetonitrile is stirred at room temperature for 16 hours. The reaction mixture is concentrated at a bath temperature of 60° C. using a rotary evaporator, and the residue is taken up in 10 ml of water. The resulting solution is adjusted to pH 7 using dilute hydrochloric acid, and the solid is filtered off. The filtrate is extracted three times using 20 ml of dichloromethane each time. The organic phase is dried over sodium sulphate and filtered and the filtrate is concentrated at a bath temperature of 60° C. using a rotary evaporator. This gives 2.4 g of a light-brown solid which has the X-ray powder diffractogram shown in FIG. 4 and is therefore predominantly amorphous.
EXAMPLE 1
1012 g of 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are initially charged in a mixture of 3300 ml of ethanol, 1980 ml of N-methyl-pyrrolidone and 534 g of Hünig base. The mixture is heated under reflux, and 459 g of (1S,6S)-2,8-diazabicyclo[4.3.0]nonane are then added dropwise. After the dropwise addition has ended, the mixture is stirred under reflux for another 3 hours and then allowed to cool to room temperature, and the solid is filtered off with suction and washed with a total of 1800 ml of ethanol.
The resulting solid is suspended in a mixture of 4650 ml of ethanol and 41 g of Hünig base, and the reaction mixture is heated under reflux for 3 hours. The reaction mixture is allowed to cool again to room temperature, and the solid is filtered off with suction, washed with a total of 1000 ml of EtOH and dried at from 60 to 70° C. in a vacuum drying cabinet until the weight remains constant. This gives 1130 g of a beige solid which has the X-ray powder diffractogram shown in FIG. 5.
From 450 g of this solid and 29,450 g of doubly distilled water, a 1.5% strength (w/w) aqueous solution is prepared, which is filtered through a 0.2 μm filter to remove any undissolved particles. This solution is then stored at room temperature under exclusion of light in canisters of polyethylene for 4 weeks. After this period of time, the precipitated solid is filtered off through a 0.8 μm filter and dried at 75° C. overnight.
This gives 2 g of a solid which, according to X-ray powder diffractogram, is predominantly amorphous (FIG. 6) and has the DTA shown in FIG. 7.
30 mg of the solid obtained in this manner are heated at 160° C. under nitrogen for 2 hours. This gives 28 mg of a solid which has the X-ray powder diffractogram shown in FIG. 1, the differential thermodiagram shown in FIG. 2 and the IR spectrum shown in FIG. 3.

Claims (10)

What is claimed is:
1. 8-Cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (CCDC) of the crystal modification D, characterized in that it has an X-ray powder diffractogram with the following reflection signals (2 theta) of high and medium intensity
2 θ (2 theta) 7.6 9.5 12.8 14.2 17.5 19 19.3 19.5 20.4 21 21.8 22.6 25.2 27.5
2. 8-Cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (CCDC) of the crystal modification D, characterized in that it has an X-ray powder diffractogram with the following reflection signals (2 theta) of high and medium intensity
2 θ (2 theta) 7.6 9.5 12.8 14.2 17.5 19 19.3 19.5 20.4 21 21.8 22.6 25.2 27.5
and a melting point, determined by DTA, of from 261° C. to 265° C.
3. 8-Cyano-1-cyclopropyl-7-(1,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic (CCDC) of the crystal modification D, obtainable by steps comprising dissolving 1 to 3 percent by weight of CCDC of unknown modification or amorpnous CCDC in water, filtering of the solid which precipitates out, drying the solid and heating it to a temperature above rearrangement temperature.
4. Process for preparing CCDC of the modification D, characterized in that 1 to 3 percent by weight of CCDC of unknown modification or amorphous CCDC is dissolved in water, and the solid which precipitates out is filtered off, dried and heated to a temperature above the rearrangement temperature.
5. A composition characterized in that it comprises, in addition to customary auxiliaries and excipients, CCDC of the modification D according to claim 1.
6. A method of preparing a composition of CCDC of the modification D according to claim 1 comprising formulating the CCDC of the modification D.
7. A process for treating bacterial infection comprising administering thereto antibacterial compositions of CCDC of the modification D according to claim 1.
8. A composition characterized in that it comprises, in addition to customary auxiliaries and excipients, CCDC of the modification D according to claim 2.
9. A method of preparing a composition of CCDC of the modification D according to claim 2 comprising formulating the CCDC of the modification D.
10. A process for treating bacterial infection comprising administering thereto antibacterial compositions of CCDC of the modification D according to claim 2.
US09/914,031 1999-02-26 2000-02-14 Crystal modification d of 8-cyano-1-cyclopropyl-7-(1s, 6s- 2,8-diazabicyclo-[4.3.0]nonan-8-yl)-6-fluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid Expired - Fee Related US6492391B1 (en)

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DE19908448A DE19908448A1 (en) 1999-02-26 1999-02-26 Crystal modification D of 8-cyan-1-cyclopropyl-7- (1S, 6S-2,8-diazabicylo [4.3.0) nonan-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3 -chino incarboxylic acid
DE19908448 1999-02-26
PCT/EP2000/001203 WO2000052010A1 (en) 1999-02-26 2000-02-14 Crystal modification d of 8-cyano-1-cyclopropyl-7- (1s, 6s- 2,8- diazabicyclo- [4.3.0] nonan-8-yl) -6-fluoro -1,4-dihydro -4-oxo -3-quinoline carboxylic acid

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Cited By (2)

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US7977484B2 (en) 2004-04-01 2011-07-12 Bayer Animal Health Gmbh Crystalline form of cyano-1-cyclopropy1-7-1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid
US10780168B2 (en) 2017-02-13 2020-09-22 Bayer Animal Health Gmbh Liquid composition containing pradofloxacin

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DE19854356A1 (en) 1998-11-25 2000-05-31 Bayer Ag Crystal modification A of 8-cyan-1-cyclopropyl-7- (1S, 6S-2,8-diazabicyclo- / 4.3.0 / nonan-8-yl) -6-fluoro-1,4-dihydro-4-oxo 3-quinoline carboxylic acid
DE19854355A1 (en) 1998-11-25 2000-05-31 Bayer Ag Crystal modification B of 8-cyan-1-cyclopropyl-7- (1S, 6S-2,8-diazabicyclo- / 4.3.O / nonan-8-yl) -6-fluoro-1,4-dihydro-4-oxo 3-quinoline carboxylic acid
DE19908449A1 (en) 1999-02-26 2000-08-31 Bayer Ag Crystal modification C of 8-cyan-1-cyclopropyl-7- (1S, 6S-2,8-diazabicylo- [4.3.0] nonan-8-yl) -6-fluoro-1,4-dihydro-4-oxo 3-chino / incarboxylic acid

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